7-alkyl-2,5-disubstituted-7h-pyrrolo(2,3-d) pyrimidine-6-carbonitriles

ABSTRACT

THE DISCLOSURE IS DIRECTED TO 7-ALKYL-2,5,6-TRISUBSTITUTED 7H-PYRROLO(2,3-D)PYRIMIDINES AND TO THE 4 - ((CYANOMETHYL)ALKYLAMINO) - 2 - SUBSTITUTED - 5 - PYRIMIDINE CARBOXYLIC ACID ESTERS WHICH ARE INTERMEDIATES IN THEIR PRODUCTION. THE COMPOUNDS HAVE CENTRAL NERVOUS SYSTEM ACTIVITY AS DEPRESSANTS. A REPRESENTATIVE COMPOUND IS 7-METHYL - 2 - PHENYL - 5 - (P-TOLYSULFONYL)-7H-PYRROLO(2,3-D)PYRIMIDINE-6-CARBONITRILE.

United States Patent What:

3,703,516 7-ALKYL-2,S-DISUBSTITUTEDJg-PYRROLOB,3-d]PYRIMIDINE-fi-CARBONITRILES Dong H. Kim, Wayne, and- Arthur A. Santilli,Havel-town,

Pa., assignors to American Home Products Corporation, New York, NY.

No Drawing. Original application Aug. 14, 1968, Ser. No. 752,486, nowPatent No. 3,575,977, dated Apr. 20, 1971. Divided and this applicationJuly 15, 1970, Ser.

Int. Cl. C07d 51/46 U.S. Cl. 260256.5 R 2 Claims ABSTRACT OF THEDISCLOSURE This application is a division of application Ser. No.752,486, filed Aug. 14, 1968 which issued as Pat. 3,575,- 977 on Apr.20, 1971.

This invention relates to new and useful pyrimidine andpyrrolo[2,3-d]pyrimidine derivatives. More particularly this inventionrelates to new and novel 7-alkyl-5- hydroxy-Z-substit-uted 7Hpyrrolo[2,3-d]pyrimidine-6- carbonitriles, to intermediates in theirpreparation: 4- [(cyanomethyl)alkylamino] 2 substituted 5pyrimidinecarboxylic acid esters, and to derivatives of the formercompounds: 7-alkyl 2,5 disubstituted-7H-pyrrole [2, 3-d]pyrimidine-G-carb onitriles.

The compounds within the purview of the present invention areexemplified by the 7 alkyl 2,5,6 trisubstituted-7H-pyrrolo[2,3-d]pyrimidines having the following formula:

where R is lower alkyl;

R is hydrogen, methyl, p-tol-uenesulfonyl or p-bromobenzenesulfonyl; and

R is lower alkyl, phenyl, halophenyl, lower alkyl phenyl r r.)

and lower alkoxyphenyl.

3,703,516 Patented Nov. 21, 1972 pyrimidine carboxylic acid estersexemplified by the following formula which, as is explained below, areintermediates in the preparation of the compounds having Formula I:

N II at NCHzCN 1%.

where R and R are defined as above; and R is methyl or ethyl.

A typical example of the compounds of this invention which are depictedby structural Formula II is 4-[(cyanomethyl)methylamino] 2 phenyl 5pyrimidinecarboxylic acid, ethyl ester.

The new and novel compounds of this invention may be prepared by theprocess which is hereinafter schematically illustrated:

N deehloroamination I HNCH2CN R N, 01

III IV (302R N CHZCN lcycllzatlon OR N OH L l R ON R- 0N N III N 1 R 1(W) where R R R and R are as defined above; and R is methyl,p-toluenesulfonyl or p-bromobenzenesulfonyl.

The 7-alkyl-5-hydroxy 2 substituted 7Hpyrrolo[2,3-d]pyrimidine-G-carbonitriles (V) of the present inventionmay be prepared in a two step process. In the first step an alkylaminoacetonitrile (IV) and a S-carbalkoxy 4 chloro 2 substituted pyrimidine(-III) are dissolved in a reaction inert organic solvent, such asalkanol or dimethylformamide, and heated at a temperature range of 60 toC., for a period of about M2 to 3 hours, affording the intermediateproduct, 4-[(cyanomethyl)alkylamino] 2 substituted 5 pyrimidinecarboxylic acid ester (11). Preferably the reaction is carried out atthe reflux temperature for about one hour in ethanol if R is ethyl or inmethanol if R is methyl.

When the reaction is complete the intermediate prod- 0 net (11) isseparated by standard recovery methods. For

instance, the inorganic salt may be removed by filtration and thefiltrate concentrated under reduced pressure. Chilling of theconcentrated solution causes separation of crystals which may becollected by filtration and washed with water to aiford the product.

Typical alkylamino-acetonitriles (IV) useful in the practice of thepresent invention are methylaminoacetonitrile, N-ethylglycinonitrile,n-butylaminoacetonitrile and the like. The acid salts of the compoundsmay also be used, such as methylaminoacetonitrile hydrochloride,provided the reaction is carried out in the presence of a base.

In the second step the 4-[(cyanomethyl)alkylamino1- 2 substitutedpyrimidinecarboxylic acid ester (II) is added to a solution of metallicsodium in ethanol where R is ethyl, or in methanol where R is methyl.The reaction mixture is heated at a temperature range of about 60 to 80degrees C. for about 15 to 180- minutes, affording the product a 7 alkyl5 hydroxy 2- substituted 7g-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (V).Preferably the reaction is carried out at the reflux temperature forabout 15 minutes. While other metals may be used, as is known in theart, sodium and potassium are preferred because they will dissolve inthe solvents used in the reaction and because they produce strong bases.

When the reaction is complete the product (V) is separated by standardrecovery methods. For instance, the reaction mixture may be evaporatedto dryness and the residue dissolved in water, acidified and filtered.The product thus obtained may be recrystallized from an appropriatesolvent, for instance, ethanol and then from chloroform.

The 7 alkyl 5 hydroxy 2-substituted-7E-pyrrolo-[2,3-d]pyrimidine-6-carbonitrile compounds (V) of this invention may befurther processed to prepare other useful compounds. For instance, thehydrogen of the S-hydroxy group may be substituted by methyl or ethylgroups, by converting the 7 alkyl 5 hydroxy-2- substituted7g-pyrrolo[2,3-d]pyrimidine-G-carbonitrile (V) to its sodium salt bytreating it with sodium methoxide or sodium ethoxide. The sodium saltthus obtained is dissolved in dimethylformamide to which methyl iodide,is added. The resulting solution is stirred for about one-half hour atroom temperature affording the product a 7 alkyl 5 methoxy 2disubstituted- 7g pyrrolo[2,3-d]pyrimidine-6-carbonitrile having thegeneral Formula VI. When the reaction is complete, the product may berecovered by well known means. For instance, the mixture may be chilledin ice and the precipitate collected on a filter and washed with water.Recrystallization from a solvent, such as dimethylformamide, affords theproduct.

Other substituents may also be used to replace the hydrogen of the5-hydroxy group. For instance p-toluenesulfonylchloride orp-bromobenzenesulfonyl chloride may be dissolved in a reaction inertorganic solvent such as ethyl ether and added dropwise with stirring, toan ice cold pyridine solution containing a 7 alkyl S-hydroxy- 2substituted 7g pyrrolo[2,3-d]pyrimidine-6-carbonitrile (V). Theresulting mixture is stirred at room temperature for about two hours,and poured into ice water, affording the appropriate 5-tosyl or S-brosylderivative product, a 7 alkyl 2,5 disubstituted-7g-pyrrolo-[2,3-d]pyrimidine 6 carbonitrile having the general Formula VI. When thereaction is complete the product may be separated by well known means,for instance the product may be collected by filtration and purified byrecrystallization from an organic solvent, such as dimethylformamide,and water to afford the product.

.All of the 4 [(cyanomethyl)alkylamino] 2 substituted 5pyrimidinecarboxylic acid esters (II) may be used as intermediates inthe preparation of 7-alkyl- 5 hydroxy 2 substituted 7g pyrrolo-[2,3-d]-pyrimidine 6 carbonitriles (V) as described above. Further, it has alsobeen found that the 4 [(cyanomethyl)-alkylamino] 2 substituted 5pyrimidinecarboxylic acid esters (II) in which the R substituent islower alkyl having up to three carbon atoms, have central nervous systemactivity as depressants. That is, they produce a calming elfect in thehost, at an orally administered dose of 127 to 400 milligrams perkilogram of host body weight when tested by the hereafter describedpharmacological test as further described below with regard to anintraperitoneally administered dose.

The 7 alkyl 2,5,6 trisubstituted 7H pyrrolo- [2,3-d]pyrirnidines (I) ofthe present invention have utility in experimental and comparativepharmacology as central nervous system depressants. That is, theyproduce a calming effect in the host at a dosage of 12.7 to 400milligrams per kilogram of host body weight as further described below.Surprisingly, the depressant activity is not noticed where the Rsubstituent is methyl and the R substituent is hydrogen or acetyl.Further, the compounds (V) and (VI) are useful also in the preparationof compounds (VII).

In the pharmacological evaluation of the biological activity of thecompounds of this invention, the in vivo effects are tested as follows.The compound is administered intraperitoneally to three mice (14 to 24grams) at each of the following doses: 400, 127, and 12.7 mg./'kg. Theanimals are watched for a minimum of two hours during which time signsof general stimulation (i.e., increased spontaneous motor activity,hyperactivity on tactile stimulation, twitching), general depression(i.e., decreased spontaneous motor activity, decreased respiration)autonomic activity (i.e., miosis, mydriasis, diarrhea) are noted.

When the compounds of this invention are employed as described above,they may be administered alone or in combination with pharmacologicallyacceptable carriers, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard pharmacological practice. For example, theymay be administered orally in the form of tablets or capsules containingsuch excipients as starch, milk, sugar, certain types of clay and soforth. They may be administered sublingually in the form of troches orlozenges in which the active ingredient is mixed with sugar and cornsyrups; and then dehydrated sufficiently to make it suitable forpressing into a solid form. They may be administered orally in the formof solutions which may contain coloring and flavoring agents or they maybe injected parenterally, that is intra-muscularly, intravenously orsubcutaneously. For parenteral administration they may be used in theform of a sterile solution containing other solutes, for example, enoughsaline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular subject under treatment. Generally, treatmentis initiated with small dosages substantially less than the optimum doseof the compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. It willgenerally be found that when the composition is administered orally,larger quantities of the active agent will be required to produce thesame effect as a smaller quantity given parenterally. In general, thecompounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects.

In order more clearly to disclose the nature of the present invention,specific examples of the practice of the invention are hereinaftergiven. It should be understood, however, that this is done solely by wayof example and is intended neither to delineate the scope of theinvention nor limit the ambit of the appended claims.

EXAMPLE 1 This examples illustrates the preparation of4-[(cyanomethyl)methylamino1-2-phenyl S-pyrimidinecarboxylic acid, ethylester, a compound of structure II.

Amixture of 10.6 grams (g.) methylaminoacetonitrile hydrochloride and 10grams of powdered sodium bicarbonate in 70 milliliters (m1.) of absoluteethanol is heated to reflux for hours (hr.) and which mechanicalstirring. 4-chloro-5-carbethoxy-Z-phenylpyrimidine (5.2 g.) is added tothe mixture and refluxing is continued for 2 hours. After being cooledto room temperature, the inorganic salt is removed by filtration, andthe filtrate is concentrated under reduced pressure. Chilling of theconcentrated solution causes separation of crystals which are collectedon a filter and washed with water several times. The crude product isrecrystallized from absolute ethanol to atford 5.5 g. of product havinga melting point of 86-88.

Based on the formula C H N it is calculated that the elemental analysisby weight would be 64.85 percent carbon, 5.44 percent hydrogen and 18.91percent nitrogen. The product is analyzed and the content is found to be65.08 percent carbon, 5.64 percent hydrogen, and 18.91 percent nitrogen.The foregoing may be expressed:

Analysis.--Calculated for C H N O (percent): C, 64.85; H, 5.44; N,18.91. Found (percent): C, 65.08; H, 5.64; N, 18.91.

EXAMPLE 2 Following the procedure of Example 1 but substitutingappropriate starting materials the following compound may be prepared:

(2) 4-[(cyanomethyl)methylamino] 2-(p-ethylphenyl)- -pyrimidinecarboxylic acid, methyl ester.

EXAMPLE 3 This example illustrates the preparation of4-[(cyanomethyl)ethylamino]-2 phenyl-5 pyrimidinecarboxylic acid, ethylester, a compound of structure II.

A mixture obtained by dissolving 15 g. of 4-chloro-5-carbethoxy-2-phenylpyrimidine and 28.4 g. of N-ethylglycinonitrile in 70ml. of absolute ethanol is refluxed for 1 hour. The amber solution istreated with charcoal and filtered. Chilling of the product causesseparation of crystals which are collected on a filter and washed withwater several times to give 14.5 g. of product. Recrystallization fromabsolute ethanol aflfords a product having a melting point of 68-70.5 C.

Analysis.Calculated for C H N O (percent): C, 65.79; H, 5.85; N, 18.05.Found (percent): C, 65.81; H, 6.12; N, 17.85.

EXAMPLES 428 Following the procedure of Examples 1-3 but usingcorrespondingly substituted starting materials in equivalent amounts inview of the material used in those examples, the following products maybe obtained:

(4) 4-[ (cyanomethyl ethylamino] -2-ethyl-5-pyrimidine carboxylic acid,ethyl ester (5 4- (cyanomethyl) propylamino]-2-methyl-5-pyrimidinecarboxylic acid, methyl ester (6) 2-butyl-4-[ (cyanomethyl)methylamino]-5-pyrimidine carboxylic acid, methyl ester (7) 2- (p-chlorophenyl) -4-(cyanomethyl ethylamino]- S-pyrimidine carboxylic acid, methyl ester (84- (cyanomethyl propylamino] -2- (o-fiuorophenyl)-5-pyrimidinecarboxylic acid, methyl ester (9) 2-(m-bromophenyl) -4-[butyl(cyanomethyl) amino]- S-pyrimidin carboxylic acid, ethyl ester 10)4- (cyanomethyl) methylamino] -2- (p-iodopheny1)- S-pyrimidinecarboxylic acid, ethyl ester (1 1 4- (cyanomethyl) ethylamino] -2-(m-tolyl) -5-pyrimidine carboxylic acid, ethyl ester 12) 2-(p-butylphenyl) -4-[ (cyanomethyl propylamino] S-pyrimidine carboxylicacid, ethyl ester 13 2-(p-butoxypl1enyl)-4-[butyl(cyanomethyl) amino]5-pyrimidine carboxylic acid, methyl ester (14) 4- (cyanomethylmethylamino] -2- (m-ethoxyphenyl)-5-pyrimidine carboxylic acid, methylester (15 4-[ (cyanomethyl) ethylamino]-2-(o-methoxyphenyl)-5-pyrimidine carboxylic acid, methyl ester 16)2-butyl-4- [butyl (cyanomethyl) amino] -5-pyrimidine carboxylic acid,ethyl ester 17) 2- (p-chlorophenyl) -4-(cyanomethyl)methylamino]-5-pyrimidine carboxylic acid, ethyl ester (18)4-[ (cyanomethyl) ethylamino] -2- (p-fluorophenyl)5-pyrimidine'carboxylic acid, ethyl ester (19) 2- (p-bromophenyl -4-(cyanomethyl) propylamino1-5-pyrimidine carboxylic acid, methyl ester(20) 4- [butyl (cyanomethyl amino] -2- (p-iodophenyl) pyrimidinecarboxylic acid, methyl ester (21) 4-[ (cyanomethyl methylamino] -2-(p-tolyl -5- pyrimidine carboxylic acid, ethyl ester (22) 2-(p-butylphenyl) -4-[ (cyanomethyl) ethylamino]- 5-pyrimidine carboxylicacid, ethyl ester (23 2- (p-butoxyphenyl -4- (cyanomethtyl)propylamino]-5-pyrimidine carboxylic acid, methyl ester (24) 4- [butyl(cyanomethyl) amino] -2- (p-ethoxyphenyl)- S-pyrimidine carboxylic acid,methyl ester (25 4- (cyanomethyl) methylamino] -2-(p-methoxyphenyl)-5-pyrimidine carboxylic acid, methyl ester (26) 4-[butyl (cyanomethyl) amino] -2- (p-ethoxyphenyl)- 5-pyrimidinecarboxylic acid, ethyl ester (27) 4-[ (cyanomethyl) propylamino]-2-ethyl-5-pyrimidine carboxylic acid, ethyl ester (28) 4-[butyl(cyanomethyl)amino]-2-(p-tolyl)-5-pyrimidine carboxylic acid,ethyl ester EXAMPLE 29 This example illustrates the preparation of4-[butyl (cyanomethyl)amino1-2-phenyl 5-pyrimidinecarboxylic acid, ethylester, a compound of structure II.

A mixture obtained by dissolving 13 g. of 4-chloro-5-carbethoxy-Z-phenylpyrimidine and 25 g. of n-butylaminoacetonitrile in100 ml. of absolute ethanol is refluxed for 45 minutes; then the excessethanol is removed under reduced pressure to give an oil. Chilling ofthe oily residue with scratching causes crystallization. The product iscollected on a filter and washed with water, then with methanol. Theproduct weighs 13.5 g. and melts at 82-84 C.

Analysis.-Calculated for C H N O (percent): C, 67.43; H, 6.55; N, 16.56.Found (percent): C, 67.73; H, 6.43; N, 16.73.

EXAMPLE 30 This examples illustrates the preparation of S-hydroxy-7-methyl-2-phenyl-7E pyrrolo[2,3-d]pyrimidine-G-carbonitrile, a compoundof structures I and V.

4-[(cyanomethyl)methylamino]-2 phenyl 5-pyrimidinecarboxylic acid, ethylester (2.9 g.) is added to a solution containing 0.23 g. of sodium in 45ml. of absolute ethanol, and the resulting mixture is refluxed for 15minutes. The reaction mixture is concentrated under reduced pressure andchilled in ice. The precipitate is collected on a filter and dissolvedin ml. of hot water. Acidification of the solution with 3 N HCl to aboutpH 2 causes separation of the product which is collected on a filter.The product weighs 2.3 g. and melts at 279- 281 C. and decomposes in themelting range. Recrystallization from absolute ethanol affords a productwhich melts at 280-283 C. and decomposes in the melting range.

Analysis-Calculated for C H N O (percent): C, 67.19; H, 4.03; N, 22.39.Found (percent): C, 67.03; H, 4.06; N, 22.49.

EXAMPLE 31 This example illustrates the preparation of 7-ethyl-S-hydroxy-2-phenyl 7g-pyrrolo[2,3-d1pyrimidine-6-carbonitrile, acompound of structures I and V.

7-ethyl-5-hydroxy-2-phenyl 7g-pyrrolo[2,3-d]pyrimidine-6-carbonitrile isprepared as in Example 30 from 4-[(cyanomethylethylamino]-2 phenyl5-pyrimidinecarboxylic acid, ethyl ester by treating with sodiumethoxide in ethanol. The crude product is recrystallized from percentethanol, then from chloroform, has a melting point of 208 C. anddecomposes at the melting point.

Analysis-Calculated for C H N O (percent): C, 68.17; H, 4.58; N, 21.20.Found (percent): C, 68.00; H, 4.63; N, 21.30.

EXAMPLE 32 This example illustrates the preparation of 7-butyl-5-hydroxy-Z-phenylflg pyrrolo[2,3-d]pyrimidine-6-carbonitrile, a compoundof structures I and V.

A mixture containing 11.1 g. of 4[butyl(cyanomethyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid, ethyl ester and 0.69 g. ofsodium in 150 ml. of absolute ethanol is refluxed for 1 hour. The excessethanol is removed under reduced pressure to dryness, and the residue isdissolved in hot water and ethanol. Acidification of the solution with 3N HCl to about pH 3 causes separation of a precipitate which iscollected on a filter and washed with water to give 10.1 g. of producthaving a melting point of 168172 C. Recrystallizations from 95% ethanolincreases the melting point to 18919l C.

Analysis.-Calculated for C H N O (percent): C, 69.84; H, 5.52; N, 19.17.Found (percent): C, 69.56; H, 5.46; N, 19.37.

EXAMPLE 33 This example illustrates the preparation of S-hydroxy-7-methyl-2-phenyl-7H pyrrolo[2,3-d]pyrimidine-6-carbonitrile, acetate, acompound of structures I and VI.

A mixture of 5-hydroxy-7-methyl-2-phenyl-7E-pyrrolo-[2,3-d]pyriniidine-6-carbonitrile (1.5 g.) and 45 ml. of aceticanhydride is refluxed for 1 hour, then chilled in ice. The crystallineproduct is collected on a filter. The product weighs 1.8 g. and melts at184-188" C. Recrystallization from acetic anhydride affords a producthaving a melting point of 188-190.5 C.

Analysis.Calculated for C H N O (percent): C, 65.75; H, 4.14; N, 19.17.Found (percent): C, 65.80; H, 4.01; N, 19.48.

EXAMPLE 34 This example illustrates the preparation of S-methoxy-7-methyl-2-phenyl 7g pyrrolo[2,3-d]pyrimidine-6-carbonitrile, a compoundof structures I and VI.

S-hydroxy 7 methyl 2 phenyl-7 11-pyrrolo[2,3-d]-pyrimidine-6-carbonitrile is converted to its sodium salt by treating itwith equal mole of sodium ethoxide in ethanol, followed by removal ofthe excess ethanol in vacuo. The sodium salt (1.7 g.) thus obtained isdissolved in 20 ml. of dimethylformamide, to which is added 1.4 g. ofmethyliodide. The resulting solution is stirred for /2 hour at roomtemperature. At this point the dark orange color disappears and crystalsseparate. The mixture is chilled in ice. The precipitate is collected ona filter, and washed with water. Addition of water to the filtratecauses separation of more product. The combined product weighs 1.2 g.and melts at l76-179 C. Recrystallization from dimethylformamide affordsa product having a melting point of 178-180.5 C.

Analysis.Calculated for C H N (percent): C, 68.17; H, 4.58; N, 21.20.Found (percent): C, 68.07; H, 4.66; N, 20.88.

EXAMPLES 35-45 Proceeding as described in Example 34 but Substitutingapropriate starting materials, the following products are aflorded:

(35) -methoxy-2-methyI-7-pro pyl-7fl-pyrrolo- 2,3 -d

pyrimidine-6-carbonitrile.

(3 6) Z-butyl-5-methoxy-7-methyl-7H -pyrrolo [2,3-d]

pyrimidine-G-carbonitrile.

(37) 2- p-chlorophenyl -7-ethyl-5 -methoxy-7 I1-pyrrolo- [2,3-d]pyrimidine-6-carbonitrile.

(3 8) 2- o-fiuorophenyl -5-methoxy-7-propyl-7g-pyrrolo- [2,3-d]pyrimidine-6-carbonitrile.

(39) 2- (m-bromophenyl -7-butyl-5-methoxy-7 I -pyrrolo- [2,3-d]pyrimidine-G-carbonitrile.

(40) 2-(p-iodophenyl)-5-methoxy-7-methyl-7g-pyrrolo-[2,3-d]pyrimidine-6-carbonitrile.

(41) 7-ethyl-5-methoxy-2-(m-tolyl)-7 l1-pyrrolo-[2,3-d]

pyrimidine-6-carbonitrile.

(42) 2-(p-butylphenyl)-5-methoxy-7-propyl-7E-pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

(43) Z-(p-butoxyphenyl)-7-butyl-5-methoxy-7g-pyrrolo [2,3 -d]pyrimidine-6-carbonitrile.

(44)Z-(m-ethoxyphenyl)-5-methoxy-7-methyl-7g-pyrrolo[2,3d]pyrimidine-6-carbonitrile.

(45) 7-ethyl-5-methoxy-2-(o-methoxyphenyl)Jg-pyrrolo [2,3-d]pyrimidine-6-carbonitrile.

EXAMPLE 46 This example illustrates the preparation of 7-methyl-2-phenyl 5 (p-tolylsulfonyl) 7E pyrrolo[2,3-d]pyrimidine-6-carbonitrile, a compound of structures I and VI.

Two and three-tenths grams of p-toluenesulfonylchloride dissolved in ml.of ether is added dropwise and with stirring to an ice-cold pyridinesolution ml.) containing 2.5 g. of 5-hydroxy-7-methyl 2phenyl-7gpyrrolo[2,3-d]pyrimidine 6 carbonitrile. The resulting mixtureis stirred at room temperature for 2 hours, then poured into ice waterwhereby a solid is deposited. The precipitate is collected on a filterand recrystallized from dimethylformamide and Water to give 2.2 g. ofproduct having a melting point of 194.5 to 197.5 C.

Analysis.-Calculated for C H N O S (percent): C, 62.63; H, 3.99; N,13.85; S, 7.93. Found (percent): C, 62.64; H, 4.03; N, 13.84; S, 7.78.

EXAMPLES 47-49 Following the procedure of Example 46 but substitutingappropriate starting materials, the following products are afforded:

(47) 5- (p-bromobenzenesulfonyl)-7-methyl-2-phenyl-7gpyrrolo [2,3-d]pyrimidine-6-carbonitrile.

(48) 2-ethyl-7-propyl-5-(p-tolylsulfonyl Jg-pyrrolo- [2,3-d]pyrimidine-6-carbonitrile.

(49) 5- (p-bromobenzenesulfonyl -7-butyl-2 (p-tolyl 7g-pyrrolo 2,3-d]pyrimidine-fi-carbonitrile.

The terms and expressions which have been employed are used as terms ofdescription and not of limitation, and there is no intention in the useof such terms and expressions of excluding any equivalents of thefeatures shown and described or portions thereof, but it is recognizedthat various modifications are possible within the scope of theinvention claimed.

What is claimed is:

1. A compound selected from those having the formula where R is loweralkyl;

R is selected from the group consisting of p-toluenesulfonyl andp-bromobenzenesulfonyl; and

R is selected from the class consisting of lower alkyl,

phenyl, halophenyl, lower alkylphenyl, and lower alkoxy phenyl. 2. Acompound as defined in claim 1 which is7-methyl-Z-phenyl-S-(p-tolylsulfonyl) 7I 1pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

References Cited UNITED STATES PATENTS 3,311,628 3/1967 Partyka 260-2564NICHOLAS S. RIZZO, Primary Examiner R. V. RUSH, Assistant Examiner

